Dysregulation of innate immune cells is thought to be the main driver of systemic Juvenile Idiopathic Arthritis (sJIA). Macrophage-derived cytokines, particularly IL-1 and IL-6, predominate within the inflammatory milieu in sJIA [4]. Differentiation of macrophages into bone resorbing osteoclasts (OCs) was responsible for persistent erosive arthritis in up to 50% of sJIA patients [5] in the pre-biologic era, and remains an issue for a significant subset of patients (CARRAnet registry data, manuscript in preparation, Mellins and colleagues). In addition, excessive activation of macrophages is observed in a severe, potentially lethal, complication of sJIA, termed macrophage activation syndrome (MAS), occurring in up to 30% of children with sJIA [6]. Thus, macrophages appear to be central players in the pathogenesis of sJIA. Unfortunately, finding effective combined treatments of both inflammatory reactions and their osteolytic consequences, without inducing global immune suppressive effects, represents the major challenge of current sJIA therapies. An efficacious approach would be to selectively target the signaling molecules controlling the inflammatory and bone resorptive effects of macrophages. We identified TMEM178, a transmembrane protein whose function has not been reported, to be a negative regulator of macrophage activation and OC formation in vitro and in vivo. The significance of this finding is buttressed by the observation that TMEM178 levels decrease in human monocytes stimulated with plasma from sJIA patients compared to healthy controls. Mechanistically, TMEM178 localizes in the endoplasmic reticulum where it binds to the calcium sensor STIM1, thereby limiting intracellular calcium fluxes in macrophages and OCs. Based on our preliminary findings we hypothesize that during sJIA, TMEM178 is required to restrain inflammatory cytokine production and OC formation via modulation of intracellular calcium signaling. Therefore, we propose to: Aim 1. Determine the importance of TMEM178 in macrophage activation in inflammatory arthritis models and sJIA samples. Aim 2. Determine the role of TMEM178 in osteoclast activation. Aim 3. Elucidate the mechanism by which TMEM178 controls macrophage and osteoclast responses. In sum, considering the reduced TMEM178 mRNA expression levels in human monocytes treated with sJIA plasma, understanding the mechanism by which TMEM178 restrains macrophage activation and OC formation could lead to the development of new strategies to treat sJIA. The results of this study could position TMEM178 as a novel gene related to development of sJIA, its complication MAS and associated erosive disease, and TMEM178 targeting may be a novel therapeutic approach.